With advances in clinical neurology and basic science research, the gap between these disciplines is narrowing. Researchers are needed to bridge this gap and apply basic science advances to clinical research and vice versa. The objective of this proposal is to produce a program combining didactic teaching, mentoring, and clinical research to allow Dr. Lomen-Hoerth to develop the skills necessary to study ALS from clinical, electrophysiological, and genetic perspectives. Among progressive motor neuron diseases, amyotrophic lateral sclerosis (ALS) is the most common affecting 1/100,000 people. ALS is a neurodegenerative disease that is inexorably progressive, with mean survival less than 4 years after diagnosis. ALS is characterized by progressive upper and lower motor neuron weakness, but survival is largely based on the degree of lower motor neuron involvement. This study will use a measure of the rate of motor neuron loss as a means of predicting prognosis. Additionally, this project will determine if relatives of sporadic ALS patients have a subclinical phenotype of ALS based on their number motor units and genetic analysis will determine if there is a heritability of the subclinical phenotype. ALS patients and age matched controls will be compared with electrophysiological studies to determine the amplitude of compound muscle action potentials, motor unit number estimates (MUNE) and fiber density of one hand muscle and one leg muscle. In ALS patients, the rate of motor unit loss will be measured and correlated with their survival. The heritability of the motor unit number will be determined by comparing the concordance of MUNE in monozygotic and dizygotic twins. The motor unit number will then be assessed in a population of siblings of sporadic cases of ALS to assess the heritability of a putative subclinical phenotype. DNA from ALS patients and their families will then be used to map susceptibility genes that are suspected to contribute to progression of sporadic ALS.